Pyrazoles are an important class of compounds in the pharmaceutical industry. Compounds containing the pyrazole motif are being developed for a wide range of therapeutic areas including CNS, metabolic diseases and endocrine functions and oncology (Elguero, J. et al. Targets in Heterocyclic Systems 2002, 6, 52-98 and reference cited therein). Several pyrazoles have been successfully commercialized, such as the blockbuster drugs sildenafil, celecoxib, and rimonabant:

Substituted pyrazoles have also been applied as novel ligands for transition metal-catalyzed cross-coupling reactions ((a) Singer, R. A. et al. Synthesis 2003, 1727-1732; (b) Singer, R. A. et al. Tetrahedron Lett. 2006, 47, 3727-3731). The synthesis of multi-substituted pyrazoles has been extensively studied, and two methods have certainly stood out in terms of generality and convenience ((a) Elguero, J. Comp. Heterocycl. Chem. 1984, 5, 167; (b) Elguero, J. Comp. Heterocycl. Chem. II 1996, 3, 1-75, 817-932; (c) Makino, K. et al. J. Heterocyl. Chem. 1998, 35, 489-497). One is the venerable Knorr reaction involving the condensation of substituted hydrazines with 1,3-diketones or their derivatives (Scheme 1A) ((a) Knorr, L. Ber. 1883, 16, 2587; (b) Patel, M. V. et al. J. Org. Chem. 2004, 69, 7058-7065; (c) Peruncheralathan, S. et al. J. Org. Chem. 2005, 70, 10030-10035).
The other method is the 1,3-dipolar cycloaddition of diazoalkanes or nitrile imines with olefins or alkynes (Scheme 1B) ((a) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565-632; (b) Padwa, A. 1,3-Dipolar Cycloaddition Chemistry; John Wiley & Sons: New York, 1984; Vol. I; (c) Padwa, A.; Pearson, W. H.; Eds. Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products; John Wiley & Sons: New York, 2002).

As successful as these two methods are in preparing pyrazoles with various substitution patterns, they are not particularly suited for the regioselective synthesis of 1,3,4-trisubstituted pyrazoles. 1,3,4-Trisubstituted pyrazoles are pharmaceutically important, yet less represented in the literature, probably due to synthetic difficulties ((a) Kira, M. A. et al. Tetrahedron Lett. 1969, 2, 109-110; (b) Stauffer, S. R. et al. Bioorg. Med. Chem. 2001, 9, 141-150; (c) Bekhit, A. A. et al. Bioorg. Med. Chem. 2004, 12, 1935-1945; (d) De Paulis, T. et al. J. Med. Chem. 2006, 49, 3332-3344). In the Knorr reaction, the condensation of substituted hydrazines with β-ketoaldehydes usually favors 1,4,5-trisubstituted pyrazoles ((a) Robertson, I. R. et al. Tetrahedron 1984, 40, 3095-3112; (b) Subramanian, L. M. et al. Synthesis 1984, 12, 1063-1065; (c) Press, J. B. et al. J. Heterocycl. Chem. 1985, 22, 561-4; (d) Muthusubramanian, L. et al. Eur. J. Med. Chem. 1986, 21, 163-166; (e) Singh, K. et al. J. Chem. Res. 2005, 8, 526-529). One solution to this issue is to prepare a 3,4-disubstituted pyrazole with hydrazine and then introduce the N-1 substituent, but this method is often not regioselective ((a) Meanwell, N. A. et al. J. Med. Chem. 1992, 35, 389-397; (b) Wang, X. et al. Org. Lett. 2000, 2, 3107-3109; (c) Patel, M. V. et al., 2004).
On the other hand, 1,3-dipolar cycloaddition reactions have been successfully employed to synthesize 1,3,4-trisubstituted pyrazoles, usually regioselectively ((a) Fathi, T. et al. Tetrahedron 1988, 44, 4527-4536; (b) Daou, B. et al. J. Heterocycl. Chem. 1989, 26, 1485-1488; (c) Lokanatha Rai, K. M. et al. Synth. Commun. 1989, 19, 2799-2807; (d) Abdallah, M. A. et al. J. Chem. Res. Syn. 1994, 2, 76-77; (e) Del Valle, J. L. et al. J. Heterocycl. Chem. 1995, 32, 899; (f) Liu, B. et al. Tetrahedron Lett. 1999, 40, 7399; (g) Molteni, G. et al. Chem. Eur. J. 2003, 9, 2770; (h) Dawood, K. M.; et al. J. Org. Chem. 2005, 70, 7537-7541). However, the difficulty generating and handling the reactive 1,3-dipoles often limits their synthetic utility. Furthermore, an additional oxidation step is often required to transform the pyrazolidine adduct to the pyrazole product.
Recently, a regioselective synthesis of 1,3,5-trisubstituted pyrazoles through reactions of hydrazones with nitroolefins under either neutral (heating in methanol (MeOH) or ethylene glycol) or acidic conditions (trifluoroacetic acid (TFA) in CF3CH2OH) was reported (Scheme 2, reaction A) (Deng, X.; Mani, N. S. Org. Lett. 2006, 8, 3505-3508). Excellent 1,3,5-regioselectivity was achieved, presumably because the aniline nitrogen atom of the hydrazone is more nucleophilic than the benzylic carbon atom, thus attacking nitroolefin preferentially. In the context of the present invention, it was hypothesized that by modulating the relative nucleophilicities of the nitrogen and the carbon atoms of the hydrazone, a novel 1,3,4-selectivity might instead be achieved. In the literature, it has been shown that the reaction of nitroolefins with diazoalkanes, in which the carbon atom is more nucleophilic, affords 3,4-disubstituted pyrazoles ((a) Parham, W. E. et al. J. Am. Chem. Soc. 1950, 72, 3843-3846; (b) Mancera, M. et al. J. Org. Chem. 1988, 53, 5648-5651; (c) Aggarwal, V. K. et al. J. Org. Chem. 2003, 68, 5381-5383). In addition, 1,3,4-trisubstituted pyrazoles were obtained as minor products from the reaction of hydrazones with nitroolefins under microwave conditions (Arrieta, A. et al. Tetrahedron 1998, 54, 13167-1318).
Based on the limitations of literature methods and the prevalence of highly substituted pyrazole components in pharmaceutical agents, a general, convenient method in the synthesis of 1,3,4-substituted pyrazoles is highly desirable. Herein, we report a novel, regioselective synthesis of 1,3,4-trisubstituted and 1,3,4,5-tetrasubstituted pyrazoles from readily available hydrazones and nitroolefins under basic conditions. This reaction is quite general for a range of substrates, and has broad functional group compatibility.